The interaction of glucose and lipid metabolism in humans is critical for maintaining normal energy balance. Diabetes has long been known to involve impairment in lipid metabolism that contributes in an ill-defined manner to the complications of the disease. J. Denis McGary, in a provocative article entitled What if Minkowski had been Ageusic? An Alternative Angle on Diabetes, (1) suggested traditional research on diabetes had the wrong emphasis and that insulin resistance and hyperglycemia might best be understood if viewed from the context of an abnormality on lipid metabolism. A decreased rate of fatty acid re-esterfication by adipose tissue could be a critical factor in regulating the delivery of fatty acids to the liver. In 1968, we first described a pathway for the re- esterfication of fatty acids in adipose tissue, termed glyceroneogenesis, that has subsequently been shown to be a significant factor in the generation of 3-glycerolphosphate required for triglyceride synthesis in both adipose tissue and liver. This pathway may play an important role in the control of triglyceride synthesis in adipose tissue and liver and control the flux of fatty acids from adipose tissue during starvation. The tissue-specific expression of the gene for the rat controlling step in this pathway, PEPCK, has been ablated in mice causing the development of fatty liver and a lack of normal growth. The research described in this grant application will explore the physiological significance of glyceroneogenesis in mammalian tissues and establish the role of PEPCK in the regulation of diabetes by controlling the rate of free fatty acid delivery to the liver. In addition, the role of PEPCK in tissue such as kidney, small intestine, brain, skeletal muscle and brown adipose tissue will be determined using genetically modified mice.